1. STI 2018 Prevention of human papillomavirus-related anal cancer
Prof Andrew Grulich
HIV Epidemiology and Prevention Program,
Kirby Institute, UNSW Australia, Sydney
21-22 July 2018

2. Disclosure Relations that could be relevant for the meeting
Company names
Sponsorship or refund funds
Sequirus, Gilead, Viiv, Hologic
Payment or other financial remuneration
Shareholder rights
None
Other relations
honoraria for educational presentations from Merck, Gilead and Viiv.
advisory board Viiv, Merck

3. Overview Anal HPV and anal cancer epidemiology
The natural history of anal high-risk HPV
Interrupting the progression of HR-HPV infection to cancer

4. Epidemiology/natural history of HPV– the basics
HPV is the most common STI
The majority of sexually active people will become infected
Mostly, initially no symptoms
except ano-genital warts caused by low-risk (LR) HPV which very rarely cause cancer
High-risk (HR) HPV infection may cause anogenital and oropharyngeal cancer
Most HR HPV infection clears within 2 years
Minority develop high-grade squamous intra-epithelial lesions
HSIL then progresses to cancer at a rate of about 1/80 per year (cervix)

5. Anal cancer is highly concentrated in few populations
Relative risk
Annual Incidence
(per 100,000)
General population
1 (referent)
1-2
Women with previous anogenital HPV disease
5-20
Organ transplant recipients
5-10
HIV negative Gay and Bisexual men (GBM)
HIV positive people (ex GBM)
10+
10-30
HIV positive GBM 50
70-130

6. Anal cancer incidence in GBM with HIV, Netherlands
O Richel et al, J AIDS 2015

7. HPV epidemiology and natural history shapes opportunities for cancer prevention

8. The natural history of HRHPV – opportunities for intervention
Normal anus
Anal HRHPV
Anal HSIL
Anal Cancer
Infection
Clearance
Progression
Regression
Invasion
HSIL = high-grade squamous intra-epithelial lesions

9. Intervention 1: HPV vaccination
Normal
Anal HRHPV
Anal HSIL
Anal Cancer
Infection
Clearance
Progression
Regression
Invasion
Primary prevention
HPV vaccination
Adolescents
Catch-up in adults (less effective)
HSIL = high-grade squamous intra-epithelial lesions

10. HPV vaccination First licensed in 2007
2-, 4- and 9-valent HPV vaccines now available
RCTS have shown that the vaccines are close to 100% effective in preventing vaccine HPV types in previously uninfected individuals
Cervix,
Vulva,
Anus,
(Oropharynx)
Prophylactic, not a therapeutic vaccine
Aimed at 9-12 year olds (prior to onset of sexual activity)

11. HPV vaccination will prevent anal cancer in the future
Young gay and bisexual men , aged 18-26
J Palefsky et al, NEJM 2011

12. HPV vaccination in adult HIV positive GBM
Safe and immunogenic
ACTG A5298: efficacy trial of the qHPV Vaccine in Older (>26) HIV-infected Adults
Trial population was majority gay men, also included women
Trial stopped early, borderline significant protective benefit
T Wilkin et al, CID 2018

13. Vaccinating females leads to substantial herd protection from HPV in heterosexual men
Proportion of Australian-born heterosexual men attending sexual health clinics
with genital warts by age group,
-51.1%
<21 years: 7.2% in 2004 increase to 12.1% in 2007 and decreased to 2.2% in 2011
21-30 years: 17% in 2004 increase to 18.2% in 2007 and declined to 8.9% in 2011
>30 years: 14.5% in 2004 decreased to 11.1% in 2007 and declined to 9.4% in 2011
-81.8%
H Ali et al, BMJ 2013

14. ……but not in homosexual men. We need to vaccinate boys
Proportion of Australian-born GBM attending sexual health clinics
with anogenital warts,
9% in 2004 and 8.5% in 2007 and 6.4% in 2011
Number of MSM seen at SHS have been increasing over the past decade – so the increase in denominator is diluting the proportion.
H Ali et al, BMJ 2013

15. Interventions 2: screening and treatment for anal HSIL
Normal
Anal HRHPV
Anal HSIL
Anal Cancer
Infection
Clearance
Progression
Regression
Invasion
Secondary prevention
Screening and treatment for HSIL
ablative or destructive therapies
Investigational therapies
immune modulators
antivirals
therapeutic HPV vaccination
HSIL = high-grade squamous intra-epithelial lesions

16. Cervical screening works: declining cancer incidence
Globocan cervical cancer fact sheet

17. Can we adapt Pap screening for anal cancer prevention?
Not recommended in any national guidelines, but practised in some US/European centres
J Palefsky, Cancer cytopath 2015

18. The cervical analogy: screening and diagnosis
Cervical cancer/HSIL
Women, general population
Screening test
Cervical Pap
Diagnostic test
Colposcopy
Threshold for referral for diagnostic test
HSIL/pHSIL
LSIL – rescreen 12/12
Sensitivity
Mean 53%
Specificity
Mean 96%
Threshold for treatment
HSIL-CIN2+.
Watchful waiting of CIN2 in the young, pregnant

19. The cervical analogy: screening and diagnosis
Cervical cancer/HSIL
Women, general population
Anal cancer/HSIL
HIV positive gay and bisexual men
Screening test
Cervical Pap
Anal swab
Diagnostic test
Colposcopy
High resolution anoscopy
Threshold for referral for diagnostic test
HSIL/pHSIL
LSIL – rescreen 12/12
Any cytological abnormality
Sensitivity
Mean 53%
55-87%
Specificity
Mean 96%
37-76%
Threshold for treatment
HSIL-CIN2+.
Watchful waiting of CIN2
in the young
Unclear.
?HSIL-AIN2+
?watchful waiting

20. The cervical analogy: HPV screening?
Cervix
Women, general population
Prevalence of HR HPV
15%
Incidence of HRHPV
Low at screening ages
Age
Prevalence peaks at <25 (30%), then declines
HR-HPV types in cancer
100% HR HPV
55% HPV16; 15% HPV18

21. The cervical analogy: HPV epidemiology
Cervix
Women, general population
Anus
HIV positive gay and bisexual men
Prevalence of HR HPV
15%
75%
Incidence of HRHPV
Low at screening ages
Few data but high (>15%/year)
Age
Prevalence peaks at <25 (30%), then declines
Prevalence constant with age, does not decline
HR-HPV types in cancer
60% HPV16
70% HPV16

22. The cervical analogy: HSIL epidemiology
High grade SIL (CIN2+)
Cervical cancer/HSIL
Women, general population
Prevalence
1-2%
Regression
CIN2: 40-50%
CIN3: 33%
Progression to cancer
CIN3: about 1 in 80/year

23. The cervical analogy: HSIL epidemiology
High grade SIL (CIN2+; AIN2+)
Cervical HSIL
Women, general population
Anal HSIL
HIV positive Gay and bisexual men
Prevalence
1-2%
30-50%
Regression
CIN2: 40-50%
CIN3: 33%
No studies, but very high prevalence suggests regression is probably common
Progression to cancer
CIN3: about 1 in 80/year (cohort data)
AIN2+: 1 in /year (estimated from cross sectional HSIL prevalence and anal cancer incidence)

24. The cervical analogy: HSIL treatment
Cervical cancer/HSIL
Women, general population
Aim of treatment
Removal of lesion and all of the transformation zone to prevent recurrence
Number of treatments for cure
Single
(failure rate around 15%)
Early morbidity
Little.
Late morbidity
Some impact on fertility

25. The cervical analogy: anal HSIL Treatment
Cervical cancer/HSIL
Women, general population
Anal cancer/HSIL
Homosexual men,
HIV positive
Aim of treatment
Removal of lesion and all of the transformation zone to prevent recurrence
Destruction of identified lesions
Complete removal is not possible
Number of treatments for cure
Single
(failure rate around 15%)
Multiple
(failure rate around 70%)
Ongoing treatment
Early morbidity
Little.
Pain, bleeding. Non-attendance at follow-up.
Late morbidity
Some impact on fertility
Poorly described.

26. HSIL clearance/persistence
12 months
Baseline
6 months
HSIL clearance
21%
HSIL- 34
HSIL- 44
HSIL+ 10
HSIL+
160
HSIL- 27
41%
HSIL+
116
HSIL persistence
56%
HSIL+ 89
393 men with complete anal cyto/histo data at
baseline, 6, and 12 months
A Grulich et al, presented at IPV Cape Town, 2017

27. Does treating HSIL prevent anal cancer?
The ANCHOR study (Prof Joel Palefsky)
Does treating anal HSIL reduce the incidence of anal cancer in HIV-infected men and women?
A variety of ablative therapies allowed including infrared coagulation, electrocautery, and TCA
US NIH funded
Estimated recruitment > 5000, 5 year follow up
Patients randomly assigned to treatment or active monitoring arms
followed six monthly for HSIL/cancer for up to 5 years
estimated completion mid 2022
ClinicalTrials.gov Identifier: NCT

28. Interventions 3: detect and treat anal cancer early
Normal
Anal HRHPV
Anal HSIL
Anal Cancer
Infection
Clearance
Progression
Regression
Invasion
Tertiary prevention
Screening for cancer
early diagnosis and curative chemo/ radiotherapy
HSIL = high-grade squamous intra-epithelial lesions

29. Digital anorectal examination (DARE)
Recommended by
European AIDS clinical society
US DHHS guidelines on prevention/treatment of opportunistic infections in people with HIV
Australasian Society for HIV medicine
May substantially advance the stage at which cancer is diagnosed, and thus improve survival and decrease treatment-related morbidity
Simple, easy to learn, but greatly under-practiced
J Ong et al, BMC Cancer 2014

30. Proven interventions now
Vaccinate!
All boys and girls prior to onset of sexual activity
9vHPV vaccination offers some (reduced) benefit in adults
Annual DARE (in HIV positive people) to diagnose anal cancer early and reduce morbidity from cancer treatment
Screening and treatment of HSIL in clinical trial settings.